1) We found that ectopic expression of a DNA synthesis enzyme, thymidylate synthase (TS) results in neoplastic transformation of mammalian cells and that catalytic activity of the enzyme is required for the development of the neoplastic phenotype. (Rahman et al Cancer Cell, 2004, Voeller et al Cell Cycle, 2005, Rahman et al CCR Frontiers, 2005). 2)We established TS transgenic animals and observed high levels of catalytically active hTS exclusively in the pancreas and low levels hTS in the spleen, stomach and heart. We found lesions of the endocrine pancreas, ranging from pancreatic islet hyperplasia to islets adenomas (Chen et al Oncogene 2006 manuscript under revision).3)In collaboration with Dr. Lipkowitz (NCI) we showed that constitutively active EGFRvIII is ubiquitinated and down-regulated by Cbl proteins. In addition, we demonstrated that Cbl can abolish transformation of NIH3T3 cells induced by EGFRvIII (Davis et al Oncogene, 2006).4)We found, in collaboration with Melinda Hollingshead (DTP) and Kent Hunter (LPG), that the DNA methylation inhibitor, zebularine, administered in drinking water to the MMTV-PvT mice resulted in a statistically significant reduction in total tumor burden as compared to the control animals. Microarray analysis of zebularine treated mammary tumors defined a set of disregulated genes that are being tested for their DNA methylation status (manuscript in preparation). 5)We found a synergistic and inhibitory effect of the DNA methylation inhibitor, zebularine, when combined with the histone deacetylase inhibitor, depsipeptide, on human breast and lung carcinoma cells. We observed that a 1000 fold lower concentration of depsipeptide was required for the synergistic effect with zebularine as compared to the MTD of depsipeptide given in the clinic (manuscript in preparation).